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Principal Investigator: Meghan Elizabeth Flanigan
Organization: UNIV OF NORTH CAROLINA CHAPEL HILL
Fiscal Year: 2024
Award: $104,106
Funding agency: National Institute on Alcohol Abuse and Alcoholism
The COVID-19 pandemic has greatly exacerbated rising patterns of excessive alcohol consumption, particularly
in women. Binge alcohol drinking is the most common pattern of excessive alcohol drinking and is associated
with increased risk of developing mood disorders and Alcohol Use Disorder (AUD). Social support strongly
buffers against alcohol craving and relapse, yet many individuals display reduced valuation of social rewards
and/or deficits in the processing of social stimuli following alcohol exposure and subsequent abstinence. This
may compound interpersonal problems in people with AUD and limit their capacity to seek out or receive social
support. Therefore, understanding the neurobiological mechanisms mediating alcohol’s effects on social
behavior is required to inform future treatments aimed at enhancing social functioning and reducing relapse in
patients with AUD. Drinking in the Dark (DiD) is a robust paradigm for investigating the circuit and molecular
mechanisms of binge-like alcohol consumption on physiology and behavior in rodents. In addition, the 3-chamber
sociability model permits the interrogation of both social reward and social recognition behaviors following
alcohol consumption. Serotonin (5-Hydroxytryptamine, 5-HT) receptor signaling in the lateral habenula (LHb)
has been implicated in the development of negative emotional states associated with abstinence from alcohol,
but the LHb remains highly understudied in the context of AUD. I recently found that DiD reduced social
recognition selectively in female mice during abstinence, and that genetic deletion of the LHb Gq-protein coupled
serotonin receptor 5HT2c partially prevented this effect. My preliminary data suggests that binge alcohol
consumption enhances the intrinsic excitability of LHb 5HT2c-containing neurons (LHb5HT2c) in the medial sub-
region, that 5-HT is released onto LHb5HT2c during social interaction, and that acute engagement of Gi signaling
in LHb5HT2c can normalize social deficits induced by alcohol. Moreover, DiD appears to modulate the expression
of multiple 5-HT receptor subtypes co-expressed in LHb5HT2c. Together, these data suggest that excessive
activation of LHb5HT2c via dysregulation of 5-HT receptor signaling may underlie social deficits induced by alcohol.
Using these preliminary findings as a foundation for the current proposal, I will 1) characterize how DiD alters
the translational and physiological landscape of LHb5HT2c projecting to the DRN (5HT2cLHb-DRN) and 2) investigate
the functional impact of genetic manipulation of 5-HT receptor sub-types in 5HT2cLHb-DRN on neuronal physiology
and DiD-induced dysregulation of social behavior. Together, these experiments will determine the effects of
binge alcohol drinking on molecular and physiological processes in 5HT2cLHb-DRN and identify novel mechanisms
by which these neurons promote social dysfunction during abstinence. Furthermore, this award will provide me
with valuable technical and professional training that will facilitate my transition to independence.
Terms: <3-D><3-Dimensional><3D><5-HT><5-HT Receptors><5-Hydroxytryptamine><5-Hydroxytryptamine Receptors><5HT><Abstinence><Acute><Address><Affective><Affective Disorders><Alcohol Chemical Class><Alcohol Drinking><Alcohol Intoxication><Alcohol abuse><Alcohol consumption><Alcohol withdrawal syndrome><Alcoholic Intoxication><Alcohols><Award><Back><Behavior><Behavioral><Brain><Brain Nervous System><Buffers><COVID crisis><COVID epidemic><COVID pandemic><COVID-19 crisis><COVID-19 epidemic><COVID-19 era><COVID-19 global health crisis><COVID-19 global pandemic><COVID-19 health crisis><COVID-19 pandemic><COVID-19 period><COVID-19 public health crisis><COVID-19 years><CRISPR><CRISPR/Cas system><Cell Body><Cell Communication and Signaling><Cell Function><Cell Nucleus><Cell Physiology><Cell Process><Cell Signaling><Cells><Cellular Function><Cellular Physiology><Cellular Process><Chronic><Clustered Regularly Interspaced Short Palindromic Repeats><Coupled><Darkness><Data><Development><Dorsum><Drunkenness><Electrophysiology><Electrophysiology (science)><Encephalon><Enteramine><Equilibrium><EtOH abuse><EtOH drinking><EtOH intoxication><EtOH use><Female><Fiber><Foundations><Future><G alpha q Protein><Galphaq Protein><Gene Expression><Generations><Genetic><Gq G-Protein><Gq Protein><Gq alpha Family G-Protein><Gαq Protein><Habenula><Heavy Drinking><Hind Brain><Hippophaine><History><Impaired Driving><Impairment><Individual><Intracellular Communication and Signaling><Investigators><Lateral><Medial><Mediating><Mice><Mice Mammals><Modeling><Molecular><Mood Disorders><Murine><Mus><Nerve Cells><Nerve Unit><Neural Cell><Neurocyte><Neurons><Neurophysiology / Electrophysiology><Nucleus><Organism-Level Process><Organismal Process><Patients><Pattern><Persons><Phase><Photometry><Physiologic><Physiologic Processes><Physiological><Physiological Adaptation><Physiological Processes><Physiology><RNA-seq using translating ribosome affinity purification><Receptor Protein><Receptor Signaling><Recording of previous events><Regulation><Relapse><Research><Research Personnel><Researchers><Rewards><Rhombencephalon><Risk><Rodent><Rodent Model><Rodentia><Rodents Mammals><Role><SARS-CoV-2 epidemic><SARS-CoV-2 global health crisis><SARS-CoV-2 global pandemic><SARS-CoV-2 pandemic><SARS-coronavirus-2 epidemic><SARS-coronavirus-2 pandemic><Serotonin><Severe Acute Respiratory Syndrome CoV 2 epidemic><Severe Acute Respiratory Syndrome CoV 2 pandemic><Severe acute respiratory syndrome coronavirus 2 epidemic><Severe acute respiratory syndrome coronavirus 2 pandemic><Signal Transduction><Signal Transduction Systems><Signaling><Social Behavior><Social Behavior Disorders><Social Functioning><Social Interaction><Social Problems><Social support><Stimulus><Subcellular Process><Substance Use Disorder><Symptoms><System><TRAP RNA sequencing><TRAP RNA-seq><TRAP-seq><Technical Expertise><Techniques><Testing><Training><Translating Ribosome Affinity Purification followed by RNA sequencing><Translating Ribosome Affinity Purification technology followed by RNA sequencing><Treatment outcome><Viral><Viral Genetics><Woman><abstaining from alcohol><abstaining from ethanol><abstinence from alcohol><abstinence from ethanol><alcohol abstinence><alcohol abuse therapy><alcohol abuse treatment><alcohol co-abuse><alcohol craving><alcohol effect><alcohol exposed><alcohol exposure><alcohol ingestion><alcohol intake><alcohol problem><alcohol product use><alcohol relapse><alcohol treatment><alcohol use><alcohol use disorder><alcohol withdrawal><alcoholic beverage consumption><alcoholic drink intake><balance><balance function><binge alcohol consumption><binge drinking><biological signal transduction><cell type><coronavirus disease 2019 crisis><coronavirus disease 2019 epidemic><coronavirus disease 2019 global health crisis><coronavirus disease 2019 global pandemic><coronavirus disease 2019 health crisis><coronavirus disease 2019 pandemic><coronavirus disease 2019 public health crisis><coronavirus disease crisis><coronavirus disease epidemic><coronavirus disease pandemic><coronavirus disease-19 global pandemic><coronavirus disease-19 pandemic><design><designing><developmental><drink heavily><drinking><driving while impaired><electrophysiological><episodic drinking><ethanol abstinence><ethanol abuse><ethanol consumption><ethanol craving><ethanol drinking><ethanol effect><ethanol exposed><ethanol exposure><ethanol ingestion><ethanol intake><ethanol intoxication><ethanol product use><ethanol relapse><ethanol use><ethanol use disorder><ethanol withdrawal><excessive alcohol consumption><excessive alcohol ingestion><excessive alcohol intake><excessive drinking><excessive ethanol ingestion><experience><experiment><experimental research><experimental study><experiments><exposed to alcohol><exposed to ethanol><exposure to alcohol><exposure to ethanol><extreme drinking><function socially><functioning social><gene manipulation><genetic manipulation><genetically manipulate><genetically perturb><hazardous alcohol use><heavy alcohol use><hindbrain><histories><impaired driving performance><in vivo><knock-down><knockdown><negative emotional state><neural control><neural regulation><neurobiological mechanism><neuromodulation><neuromodulatory><neuronal><neuronal excitability><neuroregulation><novel><overexpress><overexpression><patch clamp><prevent><preventing><problem alcohol use><problem drinking><problematic alcohol consumption><problematic alcohol use><programs><receptor><receptor expression><response><serotonin receptor><severe acute respiratory syndrome coronavirus 2 global health crisis><severe acute respiratory syndrome coronavirus 2 global pandemic><sex><skills><social><social defects><social deficits><social disorders><social disturbance><social dysfunction><social role><social support network><sociobehavior><sociobehavioral><substance use and disorder><targeted drug therapy><targeted drug treatments><targeted therapeutic><targeted therapeutic agents><targeted therapy><targeted treatment><technical skills><three dimensional><tool><transcriptomics><translating ribosome affinity purification and RNA-sequencing><translating ribosome affinity purification with RNA sequencing><translatome><virus genetics><withdrawal from alcohol>